Stroke is the third leading cause of death and a leading cause of serious, long-term disability in the United States. Although in recent years enormous progress has been made towards defining the cellular and molecular responses of the brain to ischemia, our knowledge is not yet adequate to protect against ischemic injury. No neuroprotective agents of demonstrable efficacy have yet passed clinical trials. However, we do know that calcium entry is the central feature of ischemic brain injury. Blockade of calcium entry prevents brain cell death during stroke. In a search for other effectors of brain injury in the setting of ischemia, our attention has been drawn to the recently discovered family of acid-sensing ion channels (ASICs). As acidosis is a central and prominent metabolic feature of ischemic brain and as ASICs are capable of Ca2+ permeability we have hypothesized a pathological function of ASIC's in ischemic brain injury. Members of this ion channel family respond to acidic stimuli and would therefore be activated by that central feature of ischemia, acidosis and in that setting, would flux Ca2+. Our colleagues and we have offered recent data, to include Ca2+ imaging, showing that ASIC channels flux Ca2+ in native neurons in a pH dependent manner. We have shown that this Ca2+ flux is markedly potentiated by modeled ischemia and that this Ca2+ flux is glutamate independent. ASICs are expressed throughout the mammalian central nervous system where they function in synaptic plasticity, learning and memory. Their ubiquitous presence makes them potentially important modulators of brain injury in the setting of ischemia. The discovery of ASIC blockade is the first discovery in 20 years of a new, potent mechanism to prevent calcium toxicity in acute stroke. The aim of this proposal is to advance the development of inhibitors of ASIC channels towards the creation of an acute stroke therapeutic. PUBLIC HEALTH RELEVANCE: Stroke is the third leading cause of death and a leading cause of serious, long-term disability in the United States. Blockade of calcium entry prevents brain cell death during stroke. The discovery of ASIC blockade is the first discovery in 20 years of a new, potent mechanism to prevent calcium toxicity in acute stroke.